Class IIa HDAC in Neural Activity Dependent Muscle Remodeling

A connection of class IIa HDACs to neural activity was established by the observation that HDAC4 mRNA as well as protein is dramatically induced in skeletal muscle subject to surgical denervation (Cohen et al. 2007). To a lesser extent, HDAC5 is also induced whereas MITR expression is modestly repressed (Cohen et al. 2007; Mejat et al. 2005). While an extreme condition, surgical denervation has served as a useful model to investigate how skeletal muscle responds to a loss of neural input. Accumulation of HDAC4 is clearly observed in the nucleus of denervated muscle (Cohen et al. 2007), which could contribute to a decrease in MEF2 activity upon denervation. This neural activity-dependent transcription and subcellular localization of HDAC4 opens a possibility that members of class IIa HDACs might play an important role in skeletal muscle remodeling controlled by neural activity.

After embryonic development, myofibers retain the ability to change their properties, including shape, size, and metabolic profile. For instance, during aerobic exercise, myofibers transition from type IIb to type IIa, favoring oxidative metabolism to meet functional demands. These myofibers also increase in size, termed hypertrophy. In contrast, chronically reduced neural activity associated with neu-romuscular disease, inactivity, or aging can lead to debilitating loss of muscle mass (atrophy) and a switch from oxidative fibers to glycolytic fibers, a condition that could contribute to insulin resistance. Neural input also affects synaptic gene expression and organization of neuromuscular synapses. These changes reflect alterations in gene transcription influenced by neural input. Class IIa HDACs have emerged as the critical link that connects neural signaling to all three key aspects of muscle reprogramming: fiber type specification, synaptic gene expression, and muscle fiber size regulation.

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